This RO1 renewal project will focus on targeting V?9/V?2 TCR expressing T cells for TB vaccine development. Dr. Hoft's research funded by the previous RO1 cycles has shown that BCG and other live vaccines induce memory responses in human ?9?2 T cells, distinct subsets of these ?9?2 T cells develop pathogen specificity, TB-specific ?9?2 T cells can inhibit intracellular mycobacterial growth more potenly than CD4+ or CD8+ a T cells, and TB-specific ?9?2 T cells utilize a novel protective mechanism to inhibit intracellular Mycobacterium tuberculosis (Mtb). In addition, Dr. Hoft's collaborative work with Drs. Dobos and Chatterjee (CSU) during the last RO1 cycle identified novel nonpeptidic Mtb antigens that expand TB protective subsets of ?9?2 T cells. Dr. Chen has shown that nonhuman primates (NHP) also develop protective memory ?9?2 T cells after BCG vaccination, and has greatly contributed to our knowledge of how these TB protective ?9?2 T cells function in vivo and protect against primary TB and other infections. This project will allow these productive investigators to collaborate to determine if ?9?2 T cells can provie vaccine-induced immunity protective against TB infection/disease. Three hypotheses will be tested in the following major aims: Aim #1: Identification of the specific Mtb antigens that induce TB protective ?9?2 T cells. We hypothesize that only a subset of ?9?2 T cells can recognize Mtb-infected host cells and mediate efficient protective immunity. Our considerable progress in this area already has provided new candidates for vaccine/immunotherapy development. Aim #2: Testing the hypothesis that novel antigens capable of inducing Mtb inhibitory human ?9?2 T cells can be used as prophylactic vaccines to protect against TB infection/disease in NHP. Aim #3: Identifying the detailed protective mechanisms induced by human ?9?2 T cells. We hypothesize that knowledge of the detailed mechanisms responsible for this novel host resistance pathway can be exploited as surrogate markers of protection and/or additional targets for immunotherapy development.